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Universidad Catlica Redemptoris Mater

(UNICA)
Facultad de Ciencias Mdicas
Escuela de Medicina
Patologa Humana

Atherosclerosis
Teacher: Jhoana Cruz
Students:

Marco Bolaos

David Markony

Meydeling Hernandez

Terms
Arteriosclerosis is a general term describing any hardening (and loss of elasticity) of
medium or large arteries
Arteriolosclerosis is any hardening (and loss ofelasticity) of arterioles (small
arteries);
Atherosclerosis is a hardening of an artery specifically due to an atheromatous
plaque.
Atherogenic is used for substances or processes that cause atherosclerosis.
Atherogenesis is the developmental process of atheromatous plaques.

INTRODUCTION
Definition:
Atherosclerosis
(a
rteriosclerotic vascular disease) is a
condition in which an artery wall
thickens
as
a
result
of
the
accumulation of fatty materials such
cholesterol. InGreek, athere means
sklerosmeans h ard.

as
gruel,

and

EPIDEMIOLOGY- UBIQUITOUS AMONG MOST


DEVELOPED NATIONS...LIFESTYLE AND DIET
DISEASE
MAJOR RISKS

LESSER OR UNCERTAIN RISKS

Nonmodifiable

Obesity

Increasing age

Physical inactivity

Male gender

Stress (type A personality)

Family History

Postmenopausal estrogen def.

Genetic
Abnormalities

High Carbohydrate intake

Potentially
Controllable

Lipoprotein (a)

Hyperlipidemia

Hardened (trans) unsaturated fat intake

Hypertension

Chlamydia pneumoniae infection

Cigarette smoking
Diabetes
C-reactive protein
Age-slowly progressing...take decades-middle age or later. Between ages 40 & 60,
incidence of MI in men increases fivefold.
Gender-premenopausal women realtively protected.
Genetics-multifactorial...familial clustering of risk factor e.g hypertension, diabetes,
familial hypercholesterolemia
Hyperlipidemia-hypercholesterolemia-LDL bad cholesterol. HDL good cholesterol
mobilizes cholesterol from existing atheromas and transports it to the liver for
excretion in the bile.
High dietary intake-egg yolks, butter raises plasma cholesterolOmega -3 fatty acids
beneficial (fish oils).
Raising HDL-exercise, moderate consumption of ethanol ; obesity and smoking lower
it.
Statins lower cholesterol.
Hypertension-Increase risk of IHD by 60%
Cigarette Smoking- Years of smoking one pack or more a day increases the death
rate from IHD by 200%.
Diabetes Mellitus- incidence of MI twice as high. Induces hypercholesterolemia.

Inflammation- marked by C-reactive protein. Assess systemic inflammatory


status. CRP cheap and sensitive-acute phase reactant that is synthesized by the liver.
Strongly and independently predicts the risk of MI, stroke, peripheral arterial disease,
sudden cardiac death. Lowering CRP-smoking cessation, weight loss, exercise, statins.
Hyperhomocystinemia- strong relationship between total serum homocysteine
levels and coronary artery disease, peripheral vascular disease, stroke and venous
thrombosis. Elevated levels- low folate and Vitamin B intake.

PATHOGENESIS

Response-to-injury hypothesis- 4 main stages to atherogenesis:


1.
2.
3.
4.

Chronic endothelial injury


Accumulation of lipoproteins
Resultant Inflammation & Factor release
Smooth muscle cell recruitment, proliferation and ECM production

1) CHRONIC ENDOTHELIAL
INJURY :

Hyperlipidemia

Hypertension

Smoking

Homocysteine

Hemodynamic factors

Toxins

Viruses

Immune Reactions

ENDOTHELIAL INJURY
Intimal thickening; in the presence of high-lipid diets, typical atheromas ensue. Early
human lesions begin at sites of morphologically intact endothelium. Endothelial
dysfunction underlies human atherosclerosis; in the setting of intact but dysfunctional
ECs :
1. increased endothelial permeability
2. enhanced leukocyte adhesion
3. altered gene expression

2) ACCUMULATION OF LIPOPROTEIN:
Dyslipoproteinemia
Other underlying disorder that affects the circulating
levels of lipids:
1) nephrotic
syndrome,
alcoholism,
hypothyroidism, or diabetes mellitus
2) increased LDL cholesterol levels,

3) decreased HDL cholesterol levels, and increased levels of the abnormal


Lp(a)

The evidence implicating hypercholesterolemia in atherogenesis


includes the following observations:
i. The dominant lipids in atheromatous plaques are cholesterol and cholesterol esters.
ii. Genetic
defects
in
lipoprotein
uptake
and
metabolism
that
cause
hyperlipoproteinemia are associated with accelerated atherosclerosis. Thus,
homozygous familial hypercholesterolemia, caused by defective LDL receptors
and inadequate hepatic LDL uptake, can lead to myocardial infarction before the
age of 20 years. Similarly, accelerated atherosclerosis occurs in animal models
with engineered deficiencies in apolipoproteins or LDL receptors.
iii. Other genetic or acquired disorders (e.g., diabetes mellitus, hypothyroidism) that
cause hypercholesterolemia lead to premature atherosclerosis.
iv. Epidemiologic studies demonstrate a significant correlation between the severity of
atherosclerosis and the levels of total plasma cholesterol or LDL.
v. Lowering serum cholesterol by diet or drugs slows the rate of progression of
atherosclerosis, causes regression of some plaques, and reduces the risk of
cardiovascular events.

HYPERLIPIDEMIA-MAJOR RISK FACTOR


The mechanisms :
Chronic hyperlipidemia, particularly hypercholesterolemia - increases local production
of reactive oxygen species-accelerate nitric oxide decay- local shear stress.
Lipoproteins accumulate within the intima- oxidized through the action of oxygen free
radicals (locally generated by macrophages or ECs) Oxidized LDL is ingested by
macrophages through a scavenger receptor, resulting in foam-cell formation.
In addition, oxidized LDL stimulates the release of growth factors, cytokines, and
chemokines by ECs and macrophages that increase monocyte recruitment into lesions.
Finally, oxidized LDL is cytotoxic to ECs and SMCs- EC dysfunction.
Hyperlipidemia-more specifically, hypercholesterolemia- is a major risk factor
for atherosclerosis; even in the absence of other risk factors, hypercholesterolemia is
sufficient to stimulate lesion development.
The major component of serum cholesterol associated with increased risk is lowdensity lipoprotein (LDL) cholesterol ("bad cholesterol"); LDL cholesterol has an
essential physiologic role delivering cholesterol to peripheral tissues. In contrast, highdensity lipoprotein (HDL, "good cholesterol") mobilizes cholesterol from developing
and existing atheromas and transports it to the liver for excretion in the bile.
Consequently, higher levels of HDL correlate with reduced risk.
Understandably, dietary and pharmacologic approaches that lower LDL or total serum
cholesterol, and/or raise serum HDL are all of considerable interest. High dietary
intake of cholesterol and saturated fats (present in egg yolks, animal fats, and butter,
for example) raises plasma cholesterol levels. Conversely, diets low in cholesterol
and/or with higher ratios of polyunsaturated fats lower plasma cholesterol levels.
Omega-3 fatty acids (abundant in fish oils) are beneficial, whereas (trans)unsaturated

fats produced by artificial hydrogenation of polyunsaturated oils (used in baked goods


and margarine) adversely affect cholesterol profiles.
Exercise and moderate consumption of ethanol both raise HDL levels, whereas
obesity and smoking lower it. Statins are a class of drugs that lower circulating
cholesterol levels by inhibiting hydroxymethylglutaryl coenzyme A reductase, the ratelimiting enzyme in hepatic cholesterol biosynthesis.

3)

MACROPHAGE AS THE INFLAMMATORY MEDIATOR:

Monocyte adhesion to the endothelium, followed by migration into the intima and
transformation
into
macrophages and foam cells.

Monocyte
into macrophages
is
theoretically
remove potentially
time,
accumulation of oxidized LDL

recruitment and differentiation


(and ultimately into foam cells)
protective, since these cells
harmful lipid particles. Over
however, progressive
drives
lesion

progression

Normal

vessels do not bind inflammatory cells-dysfunctional arterial ECs express adhesion


molecules; vascular cell adhesion molecule 1 (VCAM-1) in particular binds
monocytes and T cells-migrate into the intima under the influence of locally
produced chemokines.
Monocytes transform into macrophages and avidly engulf lipoproteins, including
oxidized LDL. Thus, macrophage activation (via oxidized LDL or T cells) results in
cytokine production (e.g., TNF) that further increases leukocyte adhesion and
chemokine production that in turn propel mononuclear inflammatory cell
recruitment.

INFLAMMATION:
Dysfunctional arterial ECs express VCAM-1- binds monocytes and T cells-migratechemokines.
Monocytes transform into macrophages and avidly engulf lipoproteins, including
oxidized LDL. Activated- cytokine production (e.g., TNF)-propel mononuclear
inflammatory cell recruitment.
T lymphocytes recruited to the intima- elaborate inflammatory cytokines, (e.g.,
interferon-), which in turn can stimulate macrophages as well as ECs and SMCs.
Activated leukocytes and vascular wall cells release growth factors that promote
SMC proliferation and ECM synthesis.

4) SMC PROLIFERATION AND ECM PRODUCTION:


Intimal SMC proliferation and ECM deposition
convert a fatty streak to a mature atheroma.
Intimal SMC-proliferative, synthetic
phenotype
Growth factors:

PDGF (platelets, macrophages, ECs,


and SMCs)

FGF

TGF .

SMCs synthesize ECM (notably collagen),


which stabilizes atherosclerotic plaques.
Inflammatory cells in atheromas can cause intimal SMC apoptosis, and they also
increase ECM catabolism, resulting in unstable plaques

Hypothetical sequence of cellular interactions in


atherosclerosis.
Hyperlipidemia and other risk factors are thought to cause endothelial injury, resulting
in adhesion of platelets and monocytes and release of growth factors, including
platelet-derived growth factor (PDGF), which lead to SMC migration and proliferation.
Foam cells of atheromatous plaques are derived from both macrophages and SMCsfrom macrophages via the very-low-density lipoprotein (VLDL) receptor and lowdensity lipoprotein (LDL) modifications recognized by scavenger receptors (e.g.,
oxidized LDL), and from SMCs by less certain mechanisms.
Extracellular lipid is derived from insudation from the vessel lumen, particularly in the
presence of hypercholesterolemia, and also from degenerating foam cells. Cholesterol
accumulation in the plaque reflects an imbalance between influx and efflux, and highdensity lipoprotein (HDL) probably helps clear cholesterol from these accumulations.
SMCs migrate to the intima, proliferate, and produce ECM, including collagen and
proteoglycans.

COMPLICATIONS:
1. MI
2. Rupture, Ulceration, or Erosion- thrombus formation-downstream ischaemia
3. Aneurysm-pressure or ischaemic atrophy of the underlying media, with loss of
elastic tissue-weakness
4. Arrthymias- due to scar formation
5. Mural thrombus

6.
7.
8.
9.

Atheroembolism- microemboli
Cerebral infarct
Renal infarcts
Death

If the fibrous cap separating a soft atheroma from the bloodstream within the artery
ruptures, tissue fragments are exposed and released. These tissue fragments are very
clot-promoting, containing collagen and tissue factor; they activate platelets and
activate the system of coagulation. The result is the formation of a thrombus (blood
clot) overlying the atheroma, which obstructs blood flow acutely. With the obstruction
of blood flow, downstream tissues are starved of oxygen and nutrients. If this is
the myocardium (heart muscle), angina (cardiac chest pain) or myocardial
infarction (heart attack) develops.
Signs and Symptoms:
Many times, people with atherosclerosis don't have any symptoms until an artery is
40% clogged with plaque. Symptoms vary depending upon which arteries are affected.
Coronary Artery Disease
Symptoms of coronary artery disease are usually brought on by physical exercise,
sexual activity, exposure to cold weather, anger, or stress.
The most common symptoms include:
Chest pain (generally a heavy, squeezing, or crushing sensation with
possible burning or stabbing pains)
Abdominal, neck, back, jaw, or shoulder/arm pain
Weakness
Perspiration and Shortness of breath.
Cerebrovascular Disease
Cerebrovascular disease can cause transient ischemic attack (a sudden loss of brain
function with complete recovery within 24 hours) and stroke. Symptoms may include:
Weakness or paralysis on one side of the body
Trouble speaking or understanding speech
Loss of vision in one eye
Muscle weakness
Sudden trouble walking
Dizziness
Loss of balance or coordination
Sudden severe headache
Peripheral Artery Disease
Peripheral artery disease affects the arteries that supply the arms and legs with
oxygen rich blood.
Symptoms may include:
Pain, aching, cramps, numbness or sense of fatigue in the leg
muscles (intermittent claudication)
"Bruits" (blowing sounds your doctor can hear with a stethoscope
that indicate turbulence in blood flow)
Hair loss
Thickened nails
Smooth, shiny skin surface
Skin that is cold to the touch
Gangrene

Natural history, main pathogenic events & Clinical


complications:
Fatty streaks are composed of lipid-filled foam cells but are not significantly raised and thus do not cause
any disturbance in blood flow. They begin as multiple minute yellow, flat spots that can coalesce into
elongated streaks, 1 cm long or longer. Fatty streaks can appear in the aortas of infants younger than 1
year and are present in virtually all children older than 10 years, regardless of geography, race, sex, or
environment. Coronary fatty streaks begin to form in adolescence, at the same anatomic sites that later
tend to develop plaques. The relationship of fatty streaks to atherosclerotic plaques is uncertain;
although they may evolve into precursors of plaques, not all fatty streaks are destined to become
advanced atherosclerotic lesions.